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Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up.

ABSTRACT: BACKGROUND: Efficacious immune-based therapy in treated chronic HIV-1 infection requires the induction of virus-specific CD4+ T cells and subsequent maturation and maintenance of specific memory CD8+ T cells. Concomitant daily administration of recombinant human growth hormone (rhGH) with highly active antiretroviral therapy (HAART) was used in chronically infected patients with lipodystrophy in an attempt to reconstitute these virus-specific T-cell responses. METHODS: Individuals with chronic HIV-1 infection on HAART were enrolled on a randomized, double-blinded, placebo-controlled study to receive rhGH therapy. We assessed HIV-1-specific proliferative CD4+ and interferon-gamma (IFN-gamma)-producing CD8+ T-cell responses, quantified thymic output and proviral HIV-1 DNA at the following time points: baseline; after 12 weeks of rhGH therapy; at 24 weeks, after randomization into three groups [placebo weeks 12-24 (Group A), alternate-day dosing weeks 12-24 (Group B), and twice-per-week dosing weeks 12-24 (Group C)]; and at 48 weeks after all patients had received HAART alone for the final 24 weeks. RESULTS: We found significant increases in both proliferative CD4+ and IFN-gamma-producing CD8+ HIV-1-specific T-cell responses after daily administration of rhGH. This increase was focused on HIV-1 Gag-specific T-cell responses. Following subsequent randomisation into different dosing regimens, HIV-1-specific proliferative CD4+ T-cell responses declined in patients receiving less frequent dosing of rhGH, while virus-specific IFN-gamma-producing CD8+ T-cell responses were maintained for longer periods of time. There was no significant change in thymic output and the cell-associated HIV-1 DNA remained stable in most patients. An increased anti-HIV-1 Nef-specific CD4+ T-cell proliferative response was correlated to a decrease in proviral load, and an increased HIV-1 Gag-specific IFN-gamma-producing CD8+ T-cell response correlated with an increase in proviral load. CONCLUSION: The implication of these data is that daily dosing of rhGH with HAART, in addition to improving HIV-1-associated lipodystrophy, may reverse some of the T-lymphocyte dysfunction seen in most treated HIV-1-positive patients, in a dose-dependent manner. Such immune-based therapeutic strategies used in treated, chronic HIV-1 infection may enable the induction of virus-specific CD4+ T cells essential for the subsequent 'kick-start' and expansion of virus-specific CD8+ T cells. TRIAL REGISTRATION: GH in Lipoatrophy IMP22350.

SUBMITTER: Herasimtschuk AA

PROVIDER: S-EPMC2613878 | biostudies-other | 2008

REPOSITORIES: biostudies-other

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Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up.

Herasimtschuk Anna A AA Westrop Samantha J SJ Moyle Graeme J GJ Downey Jocelyn S JS Imami Nesrina N

Journal of immune based therapies and vaccines 20081031

<h4>Background</h4>Efficacious immune-based therapy in treated chronic HIV-1 infection requires the induction of virus-specific CD4+ T cells and subsequent maturation and maintenance of specific memory CD8+ T cells. Concomitant daily administration of recombinant human growth hormone (rhGH) with highly active antiretroviral therapy (HAART) was used in chronically infected patients with lipodystrophy in an attempt to reconstitute these virus-specific T-cell responses.<h4>Methods</h4>Individuals w ...[more]

PMID: 18976455

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Project description:BackgroundIn resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks.MethodsThe Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per ?L or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736.Findings676 mother-infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5-9) than in the maternal-antiretroviral (4%, 3-6; p=0·0273) or the infant-nevirapine (4%, 2-5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29-48 weeks than during the intervention phase (1·1 [95% CI 1·0-1·2] vs 0·7 [0·7-0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group).InterpretationIn resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity.FundingUS Centers for Disease Control and Prevention.

Project description:In a previous interim 24-week virological safety analysis of the PROTEST study (1), initiation of Maraviroc (MVC) plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs) in aviremic subjects based on genotypic tropism testing of proviral HIV-1 DNA was associated with low rates of virological failure. Here we present the final 48-week analysis of the study.PROTEST was a phase 4, prospective, single-arm clinical trial (ID: NCT01378910) carried on in 24 HIV care centres in Spain. Maraviroc-naïve HIV-1-positive adults with HIV-1 RNA (VL) <50 c/mL on stable ART during the previous 6 months, requiring an ART change due to toxicity, with no antiretroviral resistance to the ART started, and R5 HIV by proviral DNA genotypic tropism testing (defined as a G2P FPR >10% in a singleton), initiated MVC with 2 NRTIs and were followed for 48 weeks. Virological failure was defined as two consecutive VL>50 c/mL. Recent adherence was calculated as: (# pills taken/# pills prescribed during the previous week)*100.Tropism results were available from 141/175 (80.6%) subjects screened: 87/141 (60%) were R5 and 74/87 (85%) were finally included in the study. Their median age was 48 years, 16% were women, 31% were MSM, 36% had CDC category C at study entry, 62% were HCV+ and 10% were HBV+. Median CD4+ counts were 616 cells/mm(3) at screening, and median nadir CD4+ counts were 143 cells/mm(3). Previous ART included PIs in 46 (62%) subjects, NNRTIs in 27 (36%) and integrase inhibitors (INIs) in 1 (2%). The main reasons for treatment change were dyslipidemia (42%), gastrointestinal symptoms (22%), and liver toxicity (15%). MVC was given alongside TDF/FTC in 40 (54%) subjects, ABC/3TC in 30 (40%), AZT/3TC in 2 (3%) and ABC/TDF in 2 (3%). Sixty-two (84%) subjects maintained VL<50 c/mL through week 48, whereas 12 (16%) discontinued treatment: two (3%) withdrew informed consent, one (1%) had a R5?X4 shift in HIV tropism between the screening and baseline visits, one (1%) was lost to follow-up, one (1%) developed an ART-related adverse event (rash), two (3%) died due to non-study-related causes (1 myocardial infarction at week 0 and 1 lung cancer at week 36), and five (7%) developed protocol-defined virological failure, although two of them regained VL<50 c/mL with the same MVC regimen (Table 1).Initiation of MVC plus 2 NRTIs in aviremic subjects based on genotypic tropism testing of proviral HIV-1 DNA is associated with low rates of virological failure up to one year.

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Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up.

Publications

Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up.

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